2. Academic Validation
  3. Discovery of a selective inhibitor of doublecortin like kinase 1

Discovery of a selective inhibitor of doublecortin like kinase 1

  • Nat Chem Biol. 2020 Jun;16(6):635-643. doi: 10.1038/s41589-020-0506-0.
Fleur M Ferguson  # 1 2,  Behnam Nabet  # 1 2,  Srivatsan Raghavan 3 4,  Yan Liu 5,  Alan L Leggett 1,  Miljan Kuljanin 6,  Radha L Kalekar 3 4,  Annan Yang 3 4,  Shuning He 7,  Jinhua Wang 1 2,  Raymond W S Ng 3 4,  Rita Sulahian 4,  Lianbo Li 5,  Emily J Poulin 8,  Ling Huang 8,  Jost Koren 9,  Nora Dieguez-Martinez 10,  Sergio Espinosa 10,  Zhiyang Zeng 11,  Cesear R Corona 11,  James D Vasta 11,  Ryoma Ohi 12,  Taebo Sim 13,  Nam Doo Kim 14,  Wayne Harshbarger 4 15,  Jose M Lizcano 10,  Matthew B Robers 11,  Senthil Muthaswamy 8 16,  Charles Y Lin 9,  A Thomas Look 7 17,  Kevin M Haigis 8 18,  Joseph D Mancias 6,  Brian M Wolpin 3 19,  Andrew J Aguirre 3 4 19,  William C Hahn 3 4 19,  Kenneth D Westover 5,  Nathanael S Gray 20 21
Affiliations

Affiliations

  • 1 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 2 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
  • 3 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 4 Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • 5 Departments of Biochemistry and Radiation Oncology, the University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 6 Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 7 Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 8 Cancer Research Institute and Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
  • 9 Department of Molecular and Human Genetics, Therapeutic Innovation Center Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, USA.
  • 10 Departament de Bioquímica i Biologia Molecular & Institut de Neurociencies, Facultat de Medicina. Universitat Autonoma de Barcelona, Bellaterra, Spain.
  • 11 Promega Corporation, Madison, WI, USA.
  • 12 Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, USA.
  • 13 Chemical Kinomics Research Center, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea and KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, Republic of Korea.
  • 14 NDBio Therapeutics Inc, Incheon, Republic of Korea.
  • 15 GSK Vaccines, Rockville, MD, USA.
  • 16 Departments of Medicine and Pathology, Harvard Medical School, Boston, MA, USA.
  • 17 Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA.
  • 18 Harvard Digestive Disease Center, Harvard Medical School, Boston, MA, USA.
  • 19 Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
  • 20 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA. nathanael_gray@dfci.harvard.edu.
  • 21 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA. nathanael_gray@dfci.harvard.edu.
  • # Contributed equally.
PMID: 32251410 DOI: 10.1038/s41589-020-0506-0
Abstract

Doublecortin Like Kinase 1 (DCLK1) is an understudied kinase that is upregulated in a wide range of cancers, including pancreatic ductal adenocarcinoma (PDAC). However, little is known about its potential as a therapeutic target. We used chemoproteomic profiling and structure-based design to develop a selective, in vivo-compatible chemical probe of the DCLK1 kinase domain, DCLK1-IN-1. We demonstrate activity of DCLK1-IN-1 against clinically relevant patient-derived PDAC Organoid models and use a combination of RNA-sequencing, proteomics and phosphoproteomics analysis to reveal that DCLK1 inhibition modulates proteins and pathways associated with cell motility in this context. DCLK1-IN-1 will serve as a versatile tool to investigate DCLK1 biology and establish its role in Cancer.

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